miR-375 maintains normal pancreatic α- and β-cell mass

Abstract

Altered growth and development of the endocrine pancreas is a frequent cause of the hyperglycemia associated with diabetes. Here we show that microRNA-375 (miR-375), which is highly expressed in pancreatic islets, is required for normal glucose homeostasis. Mice lacking miR-375 (375KO) are hyperglycemic, exhibit increased total pancreatic ␣-cell numbers, fasting and fed plasma glucagon levels, and increased gluconeogenesis and hepatic glucose output. Furthermore, pancreatic ␤-cell mass is decreased in 375KO mice as a result of impaired proliferation. In contrast, pancreatic islets of obese mice (ob/ob), a model of increased ␤-cell mass, exhibit increased expression of miR-375. Genetic deletion of miR-375 from these animals (375/ob) profoundly diminished the proliferative capacity of the endocrine pancreas and resulted in a severely diabetic state. Bioinformatic analysis of transcript data from 375KO islets revealed that miR-375 regulates a cluster of genes controlling cellular growth and proliferation. These data provide evidence that miR-375 is essential for normal glucose homeostasis, ␣-and ␤-cell turnover, and adaptive ␤-cell expansion in response to increasing insulin demand in insulin resistance.diabetes ͉ glucagon ͉ microRNA ͉ islet ͉ proliferation T he maintenance of ␤-cell mass during development and throughout life is a highly regulated process responsible for normal glucose homeostasis. Defects in the development of pancreatic islets lead to changes in islet composition, and they often result in the hyperglycemia that characterizes the diabetic state (1, 2). The dynamic adaptation of ␤-cell mass in adult life is influenced by various metabolic stresses, which control the balance between proliferation and apoptosis. These processes, known to be regulated at the transcriptional level, contribute to the development and maintenance of many tissues, including the pancreatic islet (3, 4). Recent studies have shown that microRNAs (miRNAs), which regulate gene expression at a posttranscriptional level, are powerful regulators of growth, differentiation, and organ function (5-7). For instance, mutant mice in which miRNAs are collectively silenced during endocrine pancreas development exhibit defects in all pancreatic lineages, including a dramatic reduction of insulin-producing ␤ cells (8). It is estimated that Ϸ30% of all protein coding genes are miRNA targets. Combining target prediction with experimental analysis of miRNA expression and production of loss of function mutants is beginning to improve our understanding of the roles that miRNAs play in normal and disease states (7-12). We have previously reported that miR-375, the highest expressed miRNA in pancreatic islets of humans and mice, regulates insulin secretion in isolated pancreatic ␤ cells (13). In this study we have investigated the effect of genetic ablation of miR-375 on pancreatic islet development and function and in the etiology of type 2 diabetes. Results Development of Hyperglycemia in miR-375-Null Mice.To elucidate the role of miR-375 in th...

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

“…The mouse knockout of miR-375 exhibited a decrease in β-cell mass at steady state that was further exacerbated once the model was crossed into the ob/ob background [9]. This result provided the first in vivo evidence that miRNAs could play a binary role in regulating both exocytosis and cellular proliferation.…”

“…While several sequences including miR-375, miR-7, and miR-184 appear to be enriched in the endocrine pancreas, profiling results from mouse and human tissues have shown that none of these miRNAs are entirely specific to the islet [7] [8]. In the case of miR-375, expression of this miRNA has been reported in numerous tissue types including the pituitary gland, adrenal gland, intestine, lung, and several types of cancer [9] [10]. Similarly, miR-7 and miR-184 have been shown to be highly enriched in the central nervous system and eye, respectively [11].…”

Epigenetic regulation of microRNA‐375 and its role in melanoma development in humans

“…Though miR-375 has been previously reported as important miRNA in the pancreas and brain [31][32][33], its function is not known in melanoma. We believe that the finding that miRNA-375 is epigenetically modified contributes significantly to our understanding of the events regulating melanoma development, and will eventually lead to the development of novel diagnostic and therapeutic tools.…”

Identification of microRNAs with a role in glucose stimulated insulin secretion by expression profiling of MIN6 cells

“…In recent years, miRNAs have been implicated to play a role in regulation of insulin secretion [1][2][3][4], pancreatic islet development and cell differentiation [5][6][7][8][9][10][11], insulin resistance [12][13][14][15], and have been associated with secondary complications of diabetes, such as diabetic nephropathy [16,17] and cardiovascular disease [18,19].…”